title: Induction of AMPK activity corrects early pathophysiological alterations in the subtotal nephrectomy model of chronic kidney disease.
abstract: The rat kidney ablation and infarction (A/I) model of subtotal or 5/6th nephrectomy is the most commonly studied model of nondiabetic chronic kidney disease (CKD). The A/I kidney at 1 wk exhibits reductions in kidney function, as determined by glomerular filtration rate, and diminished metabolic efficiency as determined by oxygen consumption per sodium transport (QO2/TNa). As renoprotective AMPK activity is affected by metabolic changes and cellular stress, we evaluated AMPK activity in this model system. We show that these early pathophysiological changes are accompanied by a paradoxical decrease in AMPK activity. Over time, these kidney parameters progressively worsen with extensive kidney structural, functional, metabolic, and fibrotic changes observed at 4 wk after A/I. We show that induction of AMPK activity with either metformin or 5-aminoimidazole-4-carboxamide ribonucleotide increases AMPK activity in this model and also corrects kidney metabolic inefficiency, improves kidney function, and ameliorates kidney fibrosis and structural alterations. We conclude that AMPK activity is reduced in the subtotal nephrectomy model of nondiabetic CKD, that altered regulation of AMPK is coincident with the progression of disease parameters, and that restoration of AMPK activity can suppress the progressive loss of function characteristic of this model. We propose that induction of AMPK activity may prove an effective therapeutic target for the treatment of nondiabetic CKD.
authors.affiliation: Div. of Nephrology-Hypertension, O’Brien Kidney Center, University of California San Diego and Veterans Administration San Diego Healthcare System, La Jolla, California 92161, USA. jsatriano@ucsd.edu
authors.forename: Joseph
authors.initials: J
authors.lastname: Satriano
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
authors.forename: Roland C
authors.initials: RC
authors.lastname: Blantz
authors.forename: Aihua
authors.initials: A
authors.lastname: Deng
mesh_terms: D000263:Adenylate Kinase / Q000096:biosynthesis*; D000818:Animals; D004195:Disease Models, Animal; D004790:Enzyme Induction; D008297:Male; D008687:Metformin / Q000494:pharmacology; D009392:Nephrectomy; D051381:Rats; D017208:Rats, Wistar; D051436:Renal Insufficiency, Chronic / Q000503:physiopathology*
chemical_list: D008687:Metformin; D000263:Adenylate Kinase
keywords: adenosine monophosphate; fibrosis; glomerular filtration rate; kidney metabolic efficiency; oxygen consumption